Accessible methods and tools to estimate chemical exposure in humans to support risk assessment: A systematic scoping review.

Exposure assessment is a crucial component of environmental health research, providing essential information on the potential risks associated with various chemicals. A systematic scoping review was conducted to acquire an overview of accessible human exposure assessment methods and computational tools to support and ultimately improve risk assessment. The systematic scoping review was performed in Sysrev, a web platform that introduces machine learning techniques into the review process aiming for increased accuracy and efficiency. Included publications were restricted to a publication date after the year 2000, where exposure methods were properly described. Exposure assessments methods were found to be used for a broad range of environmental chemicals including pesticides, metals, persistent chemicals, volatile organic compounds, and other chemical classes. Our results show that after the year 2000, for all the types of exposure routes, probabilistic analysis, and computational methods to calculate human exposure have increased. Sixty-three mathematical models and toolboxes were identified that have been developed in Europe, North America, and globally. However, only twelve occur frequently and their usefulness were associated with exposure route, chemical classes and input parameters used to estimate exposure. The outcome of the combined associations can function as a basis and/or guide for decision making for the selection of most appropriate method and tool to be used for environmental chemical human exposure assessments in Ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk assessment (ONTOX) project and elsewhere. Finally, the choice of input parameters used in each mathematical model and toolbox shown by our analysis can contribute to the harmonization process of the exposure models and tools increasing the prospect for comparison between studies and consistency in the regulatory process in the future.

Use of Swedish smokeless tobacco during pregnancy: A systematic review of pregnancy and early life health risk.

BACKGROUND AND AIMS: Smokeless tobacco is a heterogeneous product group with diverse composition and prevalence globally. Tobacco use during pregnancy is concerning due to the risk of adverse pregnancy outcomes and effects on child health. Nicotine may mediate several of these effects. This systematic review measured health outcomes from Swedish smokeless tobacco (snus) use during pregnancy. METHOD: Literature search was conducted by an information specialist in May 2022. We included human studies of snus use during pregnancy compared with no tobacco use, assessed risk of bias, conducted a meta-analysis and assessed confidence in effect-estimates using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). RESULTS: We included 18 cohort studies (42 to 1 006 398 participants). Snus use during pregnancy probably (moderate confidence in risk estimates) increase the risk of neonatal apnea, adjusted odds ratio 95% confidence interval [aOR (95% CI)] 1.96 (1.30 to 2.96). Snus use during pregnancy possibly (low confidence in risk estimates) increase the risk of stillbirths aOR 1.43 (1.02 to 1.99), extremely premature births aOR 1.69 (1.17 to 2.45), moderately premature birth aOR 1.26 (1.15 to 1.38), SGA aOR 1.26 (1.09 to 1.46), reduced birth weight mean difference of 72.47 g (110.58 g to 34.35 g reduction) and oral cleft malformations aOR 1.48 (1.00 to 2.21). It is uncertain (low confidence in risk estimates, CI crossing 1) whether snus use during pregnancy affects risk of preeclampsia aOR 1.11 (0.97 to 1.28), antenatal bleeding aOR 1.15 (0.92 to 1.44) and very premature birth aOR 1.26 (0.95 to 1.66). Risk of early neonatal mortality and altered heart rate variability is uncertain, very low confidence. Snus using mothers had increased prevalence of caesarean sections, low confidence. CONCLUSIONS: This systematic review reveals that use of smokeless tobacco (snus) during pregnancy may adversely impact the developing child.

Protocol for designing INVITES-IN, a tool for assessing the internal validity of in vitro studies.

This protocol describes the design and development of a tool for evaluation of the internal validity of in vitro studies, which is needed to include the data as evidence in systematic reviews and chemical risk assessments. The tool will be designed specifically to be applied to cell culture studies, including, but not restricted to, studies meeting the new approach methodology (NAM) definition. The tool is called INVITES-IN (IN VITro Experimental Studies INternal validity). In this protocol, three of the four studies that will be performed to create the release version of INVITES-IN are described. In the first study, evaluation of existing assessment tools will be combined with focus group discussions to identify how characteristics of the design or conduct of an in vitro study can affect its internal validity. Bias domains and items considered to be of relevance for in vitro studies will be identified. In the second study, group agreement on internal validity domains and items of importance for in vitro studies will be identified via a modified Delphi methodology. In the third study, the draft version of the tool will be created, based on the data on relevance and importance of bias domains and items collected in Studies 1 and 2. A separate protocol will be prepared for the fourth study, which includes the user testing and validation of the tool, and collection of users' experience.

Polycyclic aromatic hydrocarbons (PAHs) may explain the paradoxical effects of cigarette use on preeclampsia (PE).

Tobacco smoking and use of snus (smokeless tobacco) are associated with adverse effects on pregnancy and neonatal outcomes. Nicotine is considered a key toxicant involved in effects caused by both smoking and snus, while pyrolysis products including polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke represents the constituents most unequally divided between these two groups of tobacco products. The aim of this review was: i) to compare the impact, in terms of relative effect estimates, of cigarette smoking and use of Swedish snus on pregnancy outcomes using similar non-tobacco user controls, and ii) to examine whether exposure to PAHs from smoking could explain possible differences in impact on pregnancy outcomes. We systematically searched MEDLINE, Embase, PsycInfo, Web of Science and the Cochrane Database of Systematic Reviews up to October 2021 and identified studies reporting risks for adverse pregnancy and neonatal outcomes associated with snus use and with smoking relative to pregnant women with no use of tobacco. Both snus use and smoking were associated with increased risk of stillbirth, preterm birth, and oral cleft malformation, with comparable point estimates. These effects were likely due to comparable nicotine exposure. We also found striking differences. While both smoking and snus increased the risk of having small for gestational age (SGA) infants, risk from maternal smoking was markedly higher as was the reduction in birthweight. In contrast, the risk of preeclampsia (PE) was markedly lower in smokers than in controls, while snus use was associated with a slightly increased risk. We suggest that PAHs acting via AhR may explain the stronger effects of tobacco smoking on SGA and also to the apparent protective effect of cigarette smoking on PE. Possible mechanisms involved include: i) disrupted endocrine control of fetal development as well as placental development and function, and ii) stress adaption and immune suppression in placenta and mother.

Using neural networks to support high-quality evidence mapping.

BACKGROUND: The Living Evidence Map Project at the Norwegian Institute of Public Health (NIPH) gives an updated overview of research results and publications. As part of NIPH's mandate to inform evidence-based infection prevention, control and treatment, a large group of experts are continously monitoring, assessing, coding and summarising new COVID-19 publications. Screening tools, coding practice and workflow are incrementally improved, but remain largely manual. RESULTS: This paper describes how deep learning methods have been employed to learn classification and coding from the steadily growing NIPH COVID-19 dashboard data, so as to aid manual classification, screening and preprocessing of the rapidly growing influx of new papers on the subject. Our main objective is to make manual screening scalable through semi-automation, while ensuring high-quality Evidence Map content. CONCLUSIONS: We report early results on classifying publication topic and type from titles and abstracts, showing that even simple neural network architectures and text representations can yield acceptable performance.

Performance of preclinical models in predicting drug-induced liver injury in humans: a systematic review.

Drug-induced liver injury (DILI) causes one in three market withdrawals due to adverse drug reactions, causing preventable human suffering and massive financial loss. We applied evidence-based methods to investigate the role of preclinical studies in predicting human DILI using two anti-diabetic drugs from the same class, but with different toxicological profiles: troglitazone (withdrawn from US market due to DILI) and rosiglitazone (remains on US market). Evidence Stream 1: A systematic literature review of in vivo studies on rosiglitazone or troglitazone was conducted (PROSPERO registration CRD42018112353). Evidence Stream 2: in vitro data on troglitazone and rosiglitazone were retrieved from the US EPA ToxCast database. Evidence Stream 3: troglitazone- and rosiglitazone-related DILI cases were retrieved from WHO Vigibase. All three evidence stream analyses were conducted according to evidence-based methodologies and performed according to pre-registered protocols. Evidence Stream 1: 9288 references were identified, with 42 studies included in analysis. No reported biomarker for either drug indicated a strong hazard signal in either preclinical animal or human studies. All included studies had substantial limitations, resulting in "low" or "very low" certainty in findings. Evidence Stream 2: Troglitazone was active in twice as many in vitro assays (129) as rosiglitazone (60), indicating a strong signal for more off-target effects. Evidence Stream 3: We observed a fivefold difference in both all adverse events and liver-related adverse events reported, and an eightfold difference in fatalities for troglitazone, compared to rosiglitazone. In summary, published animal and human trials failed to predict troglitazone's potential to cause severe liver injury in a wider patient population, while in vitro data showed marked differences in the two drugs' off-target activities, offering a new paradigm for reducing drug attrition in late development and in the market. This investigation concludes that death and disability due to adverse drug reactions may be prevented if mechanistic information is deployed at early stages of drug development by pharmaceutical companies and is considered by regulators as a part of regulatory submissions.

Using GRADE in situations of emergencies and urgencies: certainty in evidence and recommendations matters during the COVID-19 pandemic, now more than ever and no matter what.

OBJECTIVES: The public, policy makers, and science communities are subject to many false, uninformed, overly optimistic, premature, or simply ridiculous health claims. The coronavirus disease 2019 (COVID-19) pandemic and its context is a paramount example for such claims. In this article, we describe why expressing the certainty in evidence to support a decision is critical and why the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach matters now, perhaps more than ever and no matter what the specific topic is in relation to COVID-19. We finally also offer suggestions for how it can be used appropriately to support decision-making at global, national, and local level when emergency, urgent or rapid responses are needed. STUDY DESIGN AND SETTING: This is an invited commentary to address the objectives above building on examples from the recent COVID-19 pandemic. This includes an iterative discussion of examples and development of guidance. RESULTS: The GRADE approach is a transparent and structured method for assessing the certainty of evidence and when developing recommendations that requires little additional time. We describe why emergency, urgent, or rapid responses do not justify omitting this critical assessment of the evidence. In situations of emergencies and urgencies, such as the COVID-19 pandemic, GRADE can similarly be used to express and convey certainty in intervention effects, test accuracy, risk and prognostic factors, consequences of public health measures, and qualitative bodies of evidence. CONCLUSIONS: Assessing and communicating the certainty of evidence during the COVID-19 pandemic is critical. Those offering evidence synthesis or making recommendations should use transparent ratings of the body of evidence supporting a claim regardless of time that is available or needed to provide this response.

Femoral nerve blocks for the treatment of acute pre-hospital pain: A systematic review with meta-analysis.

BACKGROUND: Pain management is one of the most important interventions in the emergency medical services. The femoral nerve block (FNB) is, among other things, indicated for pre- and post-operative pain management for patients with femoral fractures but its role in the pre-hospital setting has not been determined. The aim of this review was to assess the effect and safety of the FNB in comparison to other forms of analgesia (or no treatment) for managing acute lower extremity pain in adult patients in the pre-hospital setting. METHODS: A systematic review (PROSPERO registration (CRD42018114399)) was conducted. The Cochrane and GRADE methods were used to assess outcomes. Two authors independently reviewed each study for eligibility, extracted the data and performed risk of bias assessments. RESULTS: Four studies with a total of 252 patients were included. Two RCTs (114 patients) showed that FNB may reduce pain more effectively than metamizole (mean difference 32 mm on a 100 mm VAS (95% CI 24 to 40)). One RCT (48 patients) compared the FNB with lidocaine and magnesium sulphate to FNB with lidocaine alone and was only included here for information regarding adverse effects. One case series included 90 patients. Few adverse events were reported in the included studies. The certainty of evidence was very low. We found no studies comparing FNB to inhaled analgesics, opioids or ketamine. CONCLUSIONS: Evidence regarding the effectiveness and adverse effects of pre-hospital FNB is limited. Studies comparing pre-hospital FNB to inhaled analgesics, opioids or ketamine are lacking.

GRADE guidelines: 21 part 1. Study design, risk of bias, and indirectness in rating the certainty across a body of evidence for test accuracy.

OBJECTIVES: This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can assess the results and the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA). STUDY DESIGN AND SETTING: We present an overview of the GRADE approach and guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Part 1 of the two parts in this 21st guidance article about how to apply GRADE focuses on understanding study design issues in test accuracy, provide an overview of the domains, and describe risk of bias and indirectness specifically. RESULTS: Supplemented by practical examples, we describe how raters of the evidence using GRADE can evaluate study designs focusing on tests and how they apply the GRADE domains risk of bias and indirectness to a body of evidence of TA studies. CONCLUSION: Rating the certainty of a body of evidence using GRADE in Cochrane and other reviews and World Health Organization and other guidelines dealing with in TA studies helped refining our approach. The resulting guidance will help applying GRADE successfully for questions and recommendations focusing on tests.

GRADE guidelines: 21 part 2. Test accuracy: inconsistency, imprecision, publication bias, and other domains for rating the certainty of evidence and presenting it in evidence profiles and summary of findings tables.

OBJECTIVES: This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can rate the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA) on the domains imprecision, inconsistency, publication bias, and other domains. It also provides guidance for how to present synthesized information in evidence profiles and summary of findings tables. STUDY DESIGN AND SETTING: We present guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. RESULTS: Supplemented by practical examples, we describe how raters of the evidence can apply the GRADE domains inconsistency, imprecision, and publication bias to a body of evidence of TA studies. CONCLUSION: Using GRADE in Cochrane and other reviews as well as World Health Organization and other guidelines helped refining the GRADE approach for rating the certainty of a body of evidence from TA studies. Although several of the GRADE domains (e.g., imprecision and magnitude of the association) require further methodological research to help operationalize them, judgments need to be made on the basis of what is known so far.

Targeted mass media interventions promoting healthy behaviours to reduce risk of non-communicable diseases in adult, ethnic minorities.

BACKGROUND: Physical activity, a balanced diet, avoidance of tobacco exposure, and limited alcohol consumption may reduce morbidity and mortality from non-communicable diseases (NCDs). Mass media interventions are commonly used to encourage healthier behaviours in population groups. It is unclear whether targeted mass media interventions for ethnic minority groups are more or less effective in changing behaviours than those developed for the general population. OBJECTIVES: To determine the effects of mass media interventions targeting adult ethnic minorities with messages about physical activity, dietary patterns, tobacco use or alcohol consumption to reduce the risk of NCDs. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, ERIC, SweMed+, and ISI Web of Science until August 2016. We also searched for grey literature in OpenGrey, Grey Literature Report, Eldis, and two relevant websites until October 2016. The searches were not restricted by language. SELECTION CRITERIA: We searched for individual and cluster-randomised controlled trials, controlled before-and-after studies (CBA) and interrupted time series studies (ITS). Relevant interventions promoted healthier behaviours related to physical activity, dietary patterns, tobacco use or alcohol consumption; were disseminated via mass media channels; and targeted ethnic minority groups. The population of interest comprised adults (≥ 18 years) from ethnic minority groups in the focal countries. Primary outcomes included indicators of behavioural change, self-reported behavioural change and knowledge and attitudes towards change. Secondary outcomes were the use of health promotion services and costs related to the project. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the references to identify studies for inclusion. We extracted data and assessed the risk of bias in all included studies. We did not pool the results due to heterogeneity in comparisons made, outcomes, and study designs. We describe the results narratively and present them in 'Summary of findings' tables. We judged the quality of the evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology. MAIN RESULTS: Six studies met the inclusion criteria, including three RCTs, two cluster-RCTs and one ITS. All were conducted in the USA and comprised targeted mass media interventions for people of African descent (four studies), Spanish-language dominant Latino immigrants (one study), and Chinese immigrants (one study). The two latter studies offered the intervention in the participants' first language (Spanish, Cantonese, or Mandarin). Three interventions targeted towards women only, one pregnant women specifically. We judged all studies as being at unclear risk of bias in at least one domain and three studies as being at high risk of bias in at least one domain.We categorised the findings into three comparisons. The first comparison examined mass media interventions targeted at ethnic minorities versus an equivalent mass media intervention intended for the general population. The one study in this category (255 participants of African decent) found little or no difference in effect on self-reported behavioural change for smoking and only small differences in attitudes to change between participants who were given a culturally specific smoking cessation booklet versus a booklet intended for the general population. We are uncertain about the effect estimates, as assessed by the GRADE methodology (very low quality evidence of effect). No study provided data for indicators of behavioural change or adverse effects.The second comparison assessed targeted mass media interventions versus no intervention. One study (154 participants of African decent) reported effects for our primary outcomes. Participants in the intervention group had access to 12 one-hour live programmes on cable TV and received print material over three months regarding nutrition and physical activity to improve health and weight control. Change in body mass index (BMI) was comparable between groups 12 months after the baseline (low quality evidence). Scores on a food habits (fat behaviours) and total leisure activity scores changed favourably for the intervention group (very low quality evidence). Two other studies exposed entire populations in geographical areas to radio advertisements targeted towards African American communities. Authors presented effects on two of our secondary outcomes, use of health promotion services and project costs. The campaign message was to call smoking quit lines. The outcome was the number of calls received. After one year, one study reported 18 calls per estimated 10,000 targeted smokers from the intervention communities (estimated target population 310,500 persons), compared to 0.2 calls per estimated 10,000 targeted smokers from the control communities (estimated target population 331,400 persons) (moderate quality evidence). The ITS study also reported an increase in the number of calls from the target population during campaigns (low quality evidence). The proportion of African American callers increased in both studies (low to very low quality evidence). No study provided data on knowledge and attitudes for change and adverse effects. Information on costs were sparse.The third comparison assessed targeted mass media interventions versus a mass media intervention plus personalised content. Findings are based on three studies (1361 participants). Participants in these comparison groups received personal feedback. Two of the studies recorded weight changes over time. Neither found significant differences between the groups (low quality evidence). Evidence on behavioural changes, and knowledge and attitudes typically found some effects in favour of receiving personalised content or no significant differences between groups (very low quality evidence). No study provided data on adverse effects. Information on costs were sparse. AUTHORS' CONCLUSIONS: The available evidence is inadequate for understanding whether mass media interventions targeted toward ethnic minority populations are more effective in changing health behaviours than mass media interventions intended for the population at large. When compared to no intervention, a targeted mass media intervention may increase the number of calls to smoking quit line, but the effect on health behaviours is unclear. These studies could not distinguish the impact of different components, for instance the effect of hearing a message regarding behavioural change, the cultural adaptation to the ethnic minority group, or increase reach to the target group through more appropriate mass media channels. New studies should explore targeted interventions for ethnic minorities with a first language other than the dominant language in their resident country, as well as directly compare targeted versus general population mass media interventions.

Does turning trauma patients with an unstable spinal injury from the supine to a lateral position increase the risk of neurological deterioration?--A systematic review.

BACKGROUND: Airway protection and spinal precautions are competing concerns in the treatment of unconscious trauma patients. The placement of such patients in a lateral position may facilitate the acquisition of an adequate airway. However, trauma dogma dictates that patients should be transported in the supine position to minimize spinal movement. In this systematic review, we sought to answer the following question: Given an existing spinal injury, will changing a patient's position from supine to lateral increase the risk of neurological deterioration? METHODS: The review protocol was published in the PROSPERO database (Reg. no. CRD42012001190). We performed literature searches in PubMed, Medline, EMBASE, the Cochrane Library, CINAHL and the British Nursing Index and included studies of traumatic spinal injury, lateral positioning and neurological deterioration. The search was updated prior to submission. Two researchers independently completed each step in the review process. RESULTS: We identified 1,164 publications. However, none of these publications reported mortality or neurological deterioration with lateral positioning as an outcome measure. Twelve studies used movement of the injured spine with lateral positioning as an outcome measure; eleven of these investigations were cadaver studies. All of these cadaver studies reported spinal movement during lateral positioning. The only identified human study included eighteen patients with thoracic or lumbar spinal fractures; according to the study authors, the logrolling technique did not result in any neurological deterioration among these patients. CONCLUSIONS: We identified no clinical studies demonstrating that rotating trauma patients from the supine position to a lateral position affects mortality or causes neurological deterioration. However, in various cadaver models, this type of rotation did produce statistically significant displacements of the injured spine. The clinical significance of these cadaver-based observations remains unclear. The present evidence for harm in rotating trauma patients from the supine position to a lateral position, including the logroll maneuver, is inconclusive.

A case study of the organisation of research knowledge by systematic reviews within the mental health care field.

BACKGROUND: Our aim was to explore how systematic reviews of the effects of complex interventions within the field of organisation of mental health care organised research knowledge. METHODS: We looked up references included in 14 mental health care reviews in the database Epistemonikos to examine overlap between reviews. We classified topic concordance between study reports and reviews as similar, narrower, broader or other topic to indicate how well the research knowledge was organised. FINDINGS: We examined 182 comparisons between the theme of study reports and reviews. In 100 (55%) of the 182 comparisons, the review had a broader theme, 18 (10%) narrower, 34 (19%) similar and in 30 (16%), the review's theme was classified as 'other'. The content analysis indicated that there existed (inconsistent) overlapping of study reports between different topics. CONCLUSIONS: Within the field organisation of mental health care, there exists some unclear and inconsistent organisation of current knowledge. This may diminish the validity and reliability of systematic reviews. It is important that review authors take care in defining the review question precisely, conduct thorough literature searches, consider each study's hypothesis, disciplinary tradition and context, and if necessary, examine which other reviews have included a study in question.

A systematic review of hospital accreditation: the challenges of measuring complex intervention effects.

BACKGROUND: The increased international focus on improving patient outcomes, safety and quality of care has led stakeholders, policy makers and healthcare provider organizations to adopt standardized processes for evaluating healthcare organizations. Accreditation and certification have been proposed as interventions to support patient safety and high quality healthcare. Guidelines recommend accreditation but are cautious about the evidence, judged as inconclusive. The push for accreditation continues despite sparse evidence to support its efficiency or effectiveness. METHODS: We searched MEDLINE, EMBASE and The Cochrane Library using Medical Subject Headings (MeSH) indexes and keyword searches in any language. Studies were assessed using the Cochrane Risk of Bias Tool and AMSTAR framework. 915 abstracts were screened and 20 papers were reviewed in full in January 2013. Inclusion criteria included studies addressing the effect of hospital accreditation and certification using systematic reviews, randomized controlled trials, observational studies with a control group, or interrupted time series. Outcomes included both clinical outcomes and process measures. An updated literature search in July 2014 identified no new studies. RESULTS: The literature review uncovered three systematic reviews and one randomized controlled trial. The lone study assessed the effects of accreditation on hospital outcomes and reported inconsistent results. Excluded studies were reviewed and their findings summarized. CONCLUSION: Accreditation continues to grow internationally but due to scant evidence, no conclusions could be reached to support its effectiveness. Our review did not find evidence to support accreditation and certification of hospitals being linked to measurable changes in quality of care as measured by quality metrics and standards. Most studies did not report intervention context, implementation, or cost. This might reflect the challenges in assessing complex, heterogeneous interventions such as accreditation and certification. It is also may be magnified by the impact of how accreditation is managed and executed, and the varied financial and organizational healthcare constraints. The strategies hospitals should impelment to improve patient safety and organizational outcomes related to accreditation and certification components remains unclear.

Is the supine position associated with loss of airway patency in unconscious trauma patients? A systematic review and meta-analysis.

BACKGROUND: Airway compromise is a leading cause of death in unconscious trauma patients. Although endotracheal intubation is regarded as the gold standard treatment, most prehospital providers are not trained to perform ETI in such patients. Therefore, various lateral positions are advocated for unconscious patients, but their use remains controversial in trauma patients. We conducted a systematic review to investigate whether the supine position is associated with loss of airway patency compared to the lateral position. METHODS: The review protocol was published in the PROSPERO database (Reg. no. CRD42012001190). We performed literature searches in PubMed, Medline, EMBASE, Cochrane Library, CINAHL and British Nursing Index and included studies related to airway patency, reduced level of consciousness and patient position. We conducted meta-analyses, where appropriate. We graded the quality of evidence with the GRADE methodology. The search was updated in June 2014. RESULTS: We identified 1,306 publications, 39 of which were included for further analysis. Sixteen of these publications were included in meta-analysis. We did not identify any studies reporting direct outcome measures (mortality or morbidity) related to airway compromise caused by the patient position (lateral vs. supine position) in trauma patients or in any other patient group. In studies reporting only indirect outcome measures, we found moderate evidence of reduced airway patency in the supine vs. the lateral position, which was measured by the apnea/hypopnea index (AHI). For other indirect outcomes, we only found low or very low quality evidence. CONCLUSIONS: Although concerns other than airway patency may influence how a trauma patient is positioned, our systematic review provides evidence supporting the long held recommendation that unconscious trauma patients should be placed in a lateral position.

Effects of female genital cutting on physical health outcomes: a systematic review and meta-analysis.

OBJECTIVE: Worldwide, an estimated 125 million girls and women live with female genital mutilation/cutting (FGM/C). We aimed to systematically review the evidence for physical health risks associated with FGM/C. DESIGN: We searched 15 databases to identify studies (up to January 2012). Selection criteria were empirical studies reporting physical health outcomes from FGM/C, affecting females with any type of FGM/C, irrespective of ethnicity, nationality and age. Two review authors independently screened titles and abstracts, applied eligibility criteria, assessed methodological study quality and extracted full-text data. To derive overall risk estimates, we combined data from included studies using the Mantel-Haenszel method for unadjusted dichotomous data and the generic inverse-variance method for adjusted data. Outcomes that were sufficiently similar across studies and reasonably resistant to biases were aggregated in meta-analyses. We applied the instrument Grading of Recommendations Assessment, Development and Evaluation to assess the extent to which we have confidence in the effect estimates. RESULTS: Our search returned 5109 results, of which 185 studies (3.17 million women) satisfied the inclusion criteria. The risks of systematic and random errors were variable and we focused on key outcomes from the 57 studies with the best available evidence. The most common immediate complications were excessive bleeding, urine retention and genital tissue swelling. The most valid and statistically significant associations for the physical health sequelae of FGM/C were seen on urinary tract infections (unadjusted RR=3.01), bacterial vaginosis (adjusted OR (AOR)=1.68), dyspareunia (RR=1.53), prolonged labour (AOR=1.49), caesarean section (AOR=1.60), and difficult delivery (AOR=1.88). CONCLUSIONS: While the precise estimation of the frequency and risk of immediate, gynaecological, sexual and obstetric complications is not possible, the results weigh against the continuation of FGM/C and support the diagnosis and management of girls and women suffering the physical risks of FGM/C. TRIAL REGISTRATION NUMBER: This study is registered with PROSPERO, number CRD42012003321.

Interventions aimed at increasing the level of physical activity by including organised follow-up: a systematic review of effect.

BACKGROUND: Organised follow-up is a common feature of several strategies at the primary health care level to promote health behaviour change, e.g. to increase physical activity. In Norway, municipal 'healthy living' centres run by health care personnel are established to offer counselling and organised follow-up of health behaviour change during a 12-week programme. We report the results of a systematic review commissioned by the Norwegian Directorate of Health concerning organised follow-up to improve physical activity. METHODS: We searched ten electronic databases up to June 2012, reference lists of included publications, and relevant journals. Study selection and quality risk of bias assessment were carried out independently. Data were synthesised narratively due to heterogeneity of measurements of physical activity. The GRADE approach was used to assess our confidence in the effect estimate for each outcome in each comparison. RESULTS: Fourteen randomised controlled trials from seven countries and with a total of 5,002 participants were included in the systematic review. All studies were carried out in primary care or community settings. The interventions comprised referral to supervised group physical activity (2 studies), referral to local resources with follow-up (6 studies), and self-organised physical activity with follow-up (6 studies). The narrative synthesis, comprising a total of 39 comparisons, indicated effects of self-organised physical activity with follow-up (compared to both advice and no treatment) and referral to local resources with follow-up (compared to advice) in some of the comparisons where we rated our confidence in the effect estimates as moderate. However, the results indicated no difference between intervention and control groups for the majority of comparisons. Follow-up in the studies was mainly short-term with the longest follow-up 9 months post-treatment. We rated our confidence in the effect estimates as low or very low in most comparisons, both for positive and neutral results. CONCLUSIONS: The results of this systematic review indicate considerable uncertainty concerning effects of organised follow-up during 10-14 weeks on physical activity. Major methodological problems concerning the measurement of physical activity are discussed. TRIAL REGISTRATION: Systematic review registration: PROSPERO CRD42011001598.

Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age (Review).

BACKGROUND: Vitamin and mineral deficiencies, particularly those of iron, vitamin A and zinc, affect more than two billion people worldwide. Young children are highly vulnerable because of rapid growth and inadequate dietary practices. Micronutrient powders (MNP) are single-dose packets containing multiple vitamins and minerals in powder form that can be sprinkled onto any semi-solid food.The use of MNP for home or point-of-use fortification of complementary foods has been proposed as an intervention for improving micronutrient intake in children under two years of age. OBJECTIVES: To assess the effects and safety of home (point-of-use) fortification of foods with multiple micronutrient powders on nutritional, health and developmental outcomes in children under two years of age. SEARCH METHODS: We searched the following databases in February 2011: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (1948 to week 2 February 2011), EMBASE (1980 to Week 6 2011), CINAHL (1937 to current), CPCI-S (1990 to 19 February 2011), Science Citation Index (1970 to 19 February 2011), African Index Medicus (searched 23 February 2011), POPLINE (searched 21 February 2011), ClinicalTrials.gov (searched 23 February 2011), mRCT (searched 23 February 2011), and World Health Organization International Clinical Trials Registry Platform (ICTRP) (searched 23 February 2011). We also contacted relevant organisations (25 January 2011) for the identification of ongoing and unpublished studies. SELECTION CRITERIA: We included randomised and quasi-randomised trials with either individual or cluster randomisation. Participants were children under the age of two years at the time of intervention, with no specific health problems. The intervention was consumption of food fortified at the point of use with multiple micronutrient powders formulated with at least iron, zinc and vitamin A compared with placebo, no intervention or the use of iron containing supplements, which is the standard practice. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility of studies against the inclusion criteria, extracted data from included studies and assessed the risk of bias of the included studies. MAIN RESULTS: We included eight trials (3748 participants) conducted in low income countries in Asia, Africa and the Caribbean, where anaemia is a public health problem. The interventions lasted between two and 12 months and the powder formulations contained between five and 15 nutrients. Six trials compared the use of MNP versus no intervention or a placebo and the other two compared the use of MNP versus daily iron drops. Most of the included trials were assessed as at low risk of bias. Home fortification with MNP reduced anaemia by 31% (six trials, RR 0.69; 95% CI 0.60 to 0.78) and iron deficiency by 51% (four trials, RR 0.49; 95% CI 0.35 to 0.67) in infants and young children when compared with no intervention or placebo, but we did not find an effect on growth. In comparison with daily iron supplementation, the use of MNP produced similar results on anaemia (one trial, RR 0.89; 95% CI 0.58 to 1.39) and haemoglobin concentrations (two trials, MD -2.36 g/L; 95% CI -10.30 to 5.58); however, given the limited amount of data these results should be interpreted cautiously. No deaths were reported in the trials and information on side effects and morbidity, including malaria, was scarce. It seems that the use of MNP is efficacious among infants and young children six to 23 months of age living in settings with different prevalences of anaemia and malaria endemicity, regardless of whether the intervention lasts two, six or 12 months or whether recipients are male or female. AUTHORS' CONCLUSIONS: Home fortification of foods with multiple micronutrient powders is an effective intervention to reduce anaemia and iron deficiency in children six months to 23 months of age. The provision of MNP is better than no intervention or placebo and possibly comparable to commonly used daily iron supplementation. The benefits of this intervention as a child survival strategy or on developmental outcomes are unclear. Data on effects on malaria outcomes are lacking and further investigation of morbidity outcomes is needed. The micronutrient powders containing multiple nutrients are well accepted but adherence is variable and in some cases comparable to that achieved in infants and young children receiving standard iron supplements as drops or syrups.

The GRADE approach is reproducible in assessing the quality of evidence of quantitative evidence syntheses.

OBJECTIVE: We evaluated the inter-rater reliability (IRR) of assessing the quality of evidence (QoE) using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. STUDY DESIGN AND SETTING: On completing two training exercises, participants worked independently as individual raters to assess the QoE of 16 outcomes. After recording their initial impression using a global rating, raters graded the QoE following the GRADE approach. Subsequently, randomly paired raters submitted a consensus rating. RESULTS: The IRR without using the GRADE approach for two individual raters was 0.31 (95% confidence interval [95% CI] = 0.21-0.42) among Health Research Methodology students (n = 10) and 0.27 (95% CI = 0.19-0.37) among the GRADE working group members (n = 15). The corresponding IRR of the GRADE approach in assessing the QoE was significantly higher, that is, 0.66 (95% CI = 0.56-0.75) and 0.72 (95% CI = 0.61-0.79), respectively. The IRR further increased for three (0.80 [95% CI = 0.73-0.86] and 0.74 [95% CI = 0.65-0.81]) or four raters (0.84 [95% CI = 0.78-0.89] and 0.79 [95% CI = 0.71-0.85]). The IRR did not improve when QoE was assessed through a consensus rating. CONCLUSION: Our findings suggest that trained individuals using the GRADE approach improves reliability in comparison to intuitive judgments about the QoE and that two individual raters can reliably assess the QoE using the GRADE system.